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Some data suggest an environmental perhaps a viral factor but also of a genetic factor in the etiology of multiple sclerosis. Among the latter is the notably increased risk for a twin when the other twin has the disease, a risk further increased if they are monozygotic. There is also a greater than chance frequency of common HLA haplotypes in 2 affected siblings. The frequency of familial forms of multiple sclerosis is estimated at approximately 6 p. 100. We have studied 14 families of which 12 included 2 members with multiple sclerosis and 2 with 3 affected members. Parental relation between patients was parent to child (7 cases), brother to sister (5 cases), sister to sister including two pairs of twins (4 cases) and cousin to cousin on the mother's side (2 cases). When compared with non-familial multiple sclerosis there were no particular features in clinical disorders or course: 4 forms were progressive, the others evolving by episodes. In 26 patients in whom HLA antigens were determined, the DR2 antigen was present 19 times, the B7 antigen 9 times and the A3 antigen 7 times. In the 8 pairs of siblings with multiple sclerosis, 2 were HLA-identical and 5 semi-identical. One pair had no common haplotype. Grouping of HLA in 22 healthy members allowed 8 genealogic trees to be established. If a gene for susceptibility to multiple sclerosis exists, it is of low penetration, of dominant transmission and of limited frequency. It probably lies close to the region D of chromosome 6, because of the disequilibrium of crossed linking with A3, B7 and DR2 antigens.

A program to obtain volunteer bone marrow donors has been developed. A total of 33.000 HLA-A, B typings were performed. A search for 527 patients has been initiated. Among these, 44% are suffering from chronic myelogenous leukemia. For 23% of the patients no HLA-A, B identical donor has been identified. Out of the 401 patients who had HLA-A, B identical donor 35% (139/401) had one or more HLA-A, B, DR identical donors. In one of the transplant center, when the mixed lymphocyte culture (MLR) was carried out between 219 donors and 79 patients, a transplantation for 20/79 patients has been proposed. Up to now, transplantation has been carried out in 31 patients whom donor searches were initiated.

Study of urinary homogentisic acid and a determinantion of group HLA were carried out for 36 members of a family spread over three generations with three cases of ochronotic rheumatism in the second generation. Alkaptonuria was discovered in seven other subjects, six of them members of the third generation: urinary elimination was poor, less than 0.60 g/24 hours. There is a certain degree of consanguinity in the family studied here and these findings do not therefore rule out a recessive autosomal transmission of the alkaptonuria. They do however lead to the consideration that alkaptonuria may sometimes be found in heterozygotic subjects. A genetic relationship between HLA complex and alkaptonuria can only be claimed with difficulty from this familial study, but the high frequency of B 27 antigen (29 out of 36 members carring it) leaves room for the hypothesis that the B 27 gene, or more precisely a gene associated with the B 27 gene, plays a part in the development of ochronotic rheumatism.

Thirty members of Family C, which included cases of alkaptonuria and ochronosis, were investigated by means of HLA typing and homogentistic acid determination. The antigen HLA B27 was found in one of the two members of the first generation, in all eight members of the second generation, and in 15 of the 21 members of the third generation. Eight of 10 subjects suffering from alkaptonuria, with or without ochronotic arthropathy or spondylosis, had B27. The gene for B27 is not the gene determining homogentisic acid oxydase synthesis but this study suggests that it may be associated or linked to it.

The effector cell populations in human peripheral blood responsible for antibody-dependent cellular cytotoxicity against allogenic cells coated with HLA polyspecific antibodies were investigated using several separation techniques including preparative electrophoresis. Electrophoresis produced a marked effector cells enrichment in a range of 2--5 fractions which exhibited an intermediary electrophoretic mobility. Monocytic cells do not contribute an effector mechanism but minor subsets of polymorphonuclear cells and nylon wool non-adherent non-phagocytic lymphocytes displayed ADCC. Both effector cell populations were found to exhibit a similar electrical charge of cell surface centered around -1.05 micrometer . sec-1 V-1 cm. These observations provided a precise biophysical basis for the identification of effector cells in ADCC.

The association of ankylosing spondylarthritis with the B locus and more specifically with the B 27 antigen, is the closet known for any illness. The absence of linkage with the DRw antigens studied during this project, in 50 patients, can give rise to the hypothesis that spondylarthritis is associated with determinants situated on the B lymphocytes, linked to the HLA-B locus.

Thirty-seven patients with chronic granulocytic leukemia have been treated with supralethal chemoradiotherapy followed by transplantation of bone marrow from HLA-identical donors. All patients showed engraftment, and the Philadelphia chromosome (PH1) disappeared in each case. Four patients had syngeneic grafts before blast crisis and are still alive; 2 are in remission not maintained by therapy, and 2 others are receiving chemotherapy after having relapsed in the chronic phase. Thirty-three patients had allogeneic grafts; only 2 received the grafts during blast crisis, and neither is a long-term survivor. Of the 13 patients who had grafts in the accelerated phase, 6 died of complications related to the transplantation, and 1 died after a myeloblastic relapse. Thus 6 patients are in unmaintained remission with a median follow-up of 13 months. Eighteen patients received grafts in the chronic phase. All 10 survivors are in unmaintained remission with a median follow-up of 14 months; in this group, no patient has relapsed. The granulocytic hyperplasia of the chronic phase can be more effectively ablated than established blastic leukemia. The mortality rate of transplant-related complications must be weighted against the typical rate of progression of chronic granulocytic leukemia. Although a longer follow-up period is needed for full evaluation, bone marrow transplantation may now be offered to patients in the chronic phase in an attempt to achieve long-term survival or cure of more than one-half of these patients.

HLA A, B typing was performed in 90 patients (90 men, 10 women), and HLA DR typing in 49 patients with dilated cardiomyopathy in order to test the hypothesis that a particular genetic background may influence the immune response in that disease. No significant difference in phenotype frequency of the HLA A and B antigens was observed between patients and control population. In contrast, the HLA DR4 antigen was significantly more frequent among patients (40.8% vs 23.8%, p corrected less than 0.001). The results suggest that genetic factors play a role in the pathogenesis of dilated cardiomyopathy, and that since DR4 is frequently associated with auto-immune manifestations, a modified immune response is possible in dilated cardiomyopathy.

HLA-A B and DR typing were performed in 77 patients with AIDS related complex (ARC)--69 lymphadenopathy associated syndrome and 8 thrombocytopenic purpura LAV/HTLV III related--and 21 symptom free homosexual males. A significant increase in the frequency of HLA DR5 antigen was observed in patients with ARC mainly in purpura thrombocytopenic patients. We suggest that increase of HLA DR5 antigen support the view that DR5 antigen could be one of the factors necessary at the spreading out clinical symptoms.

A study of HLA complex (HLA A, B, C, DRw, Bf, chiddo) in monozygous twins suffering from ankylosing spondylitis with different clinical courses. All the markers studied were identified. The results would tend to suggest that hereditary factors are not alone responsible in the course of ankylosing spondylitis. Furthermore, they are not the sole causative factor of the disease since the literature contains reports of discordant pairs of twins.

The complexity of host-graft interactions after bone marrow transplantation explains the criteria of choice of the donor. Graft rejection, graft-versus-host disease, graft-versus-leukemia, delayed immune reconstitution, often associated or mutually exclusive are observed even with an HLA identical sibling donor. Syngeneic transplants may be complicated by leukemic relapse related to the loss of the graft-versus-leukemia effect. The compilation of files of unrelated donors increases the possibility of finding a matched unrelated donor. Preliminary results suggest that clinical results may be equivalent to those achieved with HLA identical sibling donors. Overall results of HLA mismatched transplants are disappointing because of the increase of immunological complications. Attempts at preventing graft-versus-host disease with T cell depletion led to an increase of immunological complications: rejection and leukemic relapse. Modifications of the conditioning regimen and use of in vivo monoclonal antibodies are currently being investigated. Ethical, legal, and psychological considerations have also to be taken into account in the donor choice especially with the increase of the donor pool.